PROJECT SUMMARY Normal aging is associated with the development of low-grade chronic neuroinflammation that contributes to cognitive decline and several age-related pathologies. Presently, there is a gap in the knowledge about what factors initiate and sustain neuroinflammation. Until these mechanisms are elucidated, the ability to develop effective therapies to treat and/or prevent age-associated disorders that have an inflammatory component will likely be unattainable. The long-term goal is to identify the physiological mechanisms and functional consequences of neuroinflammation in aged subjects. The objective of the current application is to identify the immune receptor(s) that triggers the development and maintenance of chronic inflammation in the aged brain. The central hypothesis is that activation of a Toll-like receptor (TLR), an immune pattern recognition receptor, initiates and sustains the neuroinflammatory state that develops with aging. The rationale for this work is that discovering the immune receptor that mediates the development of the chronic neuroinflammation will facilitate the identification of the activating ligand(s) and provide novel therapeutic targets to treat persistent neuroinflammation. Guided by preliminary data, this hypothesis will be tested through completion of the following specific aims: 1) Identify the immune receptor that promotes the development and maintenance of age-related neuroinflammation. 2) Determine the therapeutic potential of TLR-4 inhibition to alleviate age- related deficits in cognitive function and neural plasticity. The objective for Aim 1 is to directly test whether eliminating TLR-4 activation in a region- and cell-specific manner prevents the onset and maintenance of age- related neuroinflammation. To accomplish this objective, the approach is to employ global and conditional knockout (KO) models and selective TLR-4 inhibitory antibodies to test whether a complete, peripheral, or microglia-specific deficiency in TLR-4 reduces neuroinflammation. For Aim 2, the approach is to assess alterations in memory and neural plasticity in aged mice following pharmacological inhibition of TLR-4. Further, immunofluorescence will be used to assess hippocampal neurogenesis in global and microglia-specific KO mice. Completion of Aim 2 will determine the role of TLR activation in mediating age-related cognitive and neural plasticity deficits as well as the cell-specific function of TLR-4 on microglia in regulating neurogenesis. The proposal is innovative because it is the first to determine whether TLR activation mediates the development of neuroinflammation in the aged and employs a novel cell-specific conditional KO model that will determine the contribution of TLR-4 on microglial cells to the progression of neuroinflammation. The proposed research is significant because it is expected to facilitate development of novel preventative and therapeutic treatments as well as expedite the identification of the ligand(s) that activate the immune system in aged individuals. Ultimately, such knowledge is expected to accelerate the development of efficacious treatments for neuroinflammation that will likely improve general health and decrease the risk of neurodegeneration.